Cyclodextrin polymers for carrying and releasing drugs

• US 6,048,736 A
• Filed: 12/30/1998
• Issued: 04/11/2000
• Est. Priority Date: 04/29/1998
• Status: Expired due to Fees

• Current Assignee: Kenneth M. Kosak
• Original Assignee: Kenneth M. Kosak
• Inventors: Kosak, Kenneth M.
• Primary Examiner(s): Stucker, Jeffrey
• Assistant Examiner(s): NELSON, BRETT L
• Application Number:
  US09/223,055
• Time in Patent Office: 468 Days
• Field of Search: 436/536, 436/507, 514/58
• US Class Current: 436/536
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Abstract

This invention discloses methods for preparing compositions of cyclodextrin polymers for carrying drugs and other active agents. Methods are also disclosed for preparing cyclodextrin polymer carriers that release drugs under controlled conditions. The invention also discloses methods for preparing compositions of cyclodextrin polymer carriers that are coupled to biorecognition molecules for targeting the delivery of drugs to their site of action.

The advantages of the water soluble (or colloidal) cyclodextrin polymer carrier are:

(1) Drugs can be used that are designed for efficacy without conjugation requirements.

(2) It will allow the use of drugs designed solely for efficacy without regard for solubility.

(3) Unmodified drugs can be delivered as macromolecules and released within the cell.

(4) Drugs can be targeted by coupling the carrier to biorecognition molecules.

(5) Synthesis methods are independent of the drug to facilitate multiple drug therapies.

Claims

1. A method for producing a controlled release pharmaceutical composition comprising;

a) combining cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers with an active agent selected from the group consisting of anticancer drugs, antineoplastic drugs, antifungal drugs, antibacterial drugs, antiviral drugs, cardiac drugs, neurological drugs, alkaloids, antibiotics, bioactive peptides, steroids, steroid hormones, polypeptide hormones, interferons, interleukins, narcotics, prostaglandins, purines, pyrimidines, anti-protozoan drugs and anti-parasitic drugs to form an inclusion complex between the cyclodextrin molecules and the active agent, and

b) covalently cross-linking the cyclodextrin molecules through a biocleavable linkage selected from the group consisting of a disulfide linkage, a protected disulfide linkage, an ester linkage and a hydrazone linkage, to form a polymer that has completely entrapped the active agent and wherein the cross-linking provides the function of controlled release.

2. The method of claim 1 further comprising the step of coupling a biorecognition molecule to the pharmaceutical.

3. The method of claim 1 wherein the active agent is selected from the group consisting of ganciclovir, furosemide, indomethacin, chlorpromazine, methotrexate, penicillin derivatives, anthracyclines, teramycins, tetracyclines, chlorotetracyclines, clomocyclines, butoconazole, ellipticines, guamecyclines, macrolides, filipins, fungichromins, nystatins, 5'"'"'-fluorouracil, 5'"'"'-fluoro-2'"'"'-deoxyuridine, allopurinol and paclitaxel.

4. A method for producing a controlled release pharmaceutical composition comprising;

a) combining cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers with an active agent consisting of a nucleic acid, to form an inclusion complex between the cyclodextrin molecules and the active agent, and

b) covalently cross-linking the cyclodextrin molecules through a biocleavable linkage selected from the group consisting of a disulfide linkage, a protected disulfide linkage, an ester linkage and a hydrazone linkage, to form a polymer that has completely entrapped the active agent and wherein the cross-linking provides the function of controlled release.

5. The method of claim 4 further comprising the step of coupling a biorecognition molecule to the pharmaceutical.

6. The method of claim 4 wherein the nucleic acid is selected from the group consisting of DNA, RNA, antisense oligonucleotides, phosphorthioate oligonucleotides, synthetic nucleic acid polymers and peptide nucleic acids.

7. A method for producing a controlled release pharmaceutical composition comprising;

a) combining cyclodextrin molecules selected from the group consisting of cyclodextrin derivatives, cyclodextrin dimers, cyclodextrin trimers, and cyclodextrin polymers with an active agent consisting of a toxin, to form an inclusion complex between the cyclodextrin molecules and the active agent, and

b) covalently cross-linking the cyclodextrin molecules through a biocleavable linkage selected from the group consisting of a disulfide linkage, a protected disulfide linkage, an ester linkage and a hydrazone linkage, to form a polymer that has completely entrapped the active agent and wherein the cross-linking provides the function of controlled release.

8. The method of claim 7 further comprising the step of coupling a biorecognition molecule to the pharmaceutical.

9. The method of claim 7 wherein the toxin is selected from the group consisting of aflatoxins, ricins, bungarotoxins, irinotecan, pesticides, cevadines, desatrines, veratridine and cevine derivatives.